Drug combo doesn't benefit depression but leaves room for doubt

A large clinical trial led by researchers at the Universities of Bristol, Exeter, Keele, Manchester and Hull York Medical School, and published in the British Medical Journal has found that a popular combination of antidepression drugs was no more effective in improving depression than a placebo. The studies' author's call on doctors to rethink their use.

Psychiatrists and GPs increasingly combine mirtazapine with an SSRI (selective serotonin reuptake inhibitor) or SNRI (serotonin-noradenaline reuptake inhibitor) antidepressant for patients whose depression does not respond to a single antidepressant.

The trial led looked at the effectiveness of adding mirtazapine to an SSRI or SNRI in patients who remain depressed after at least six weeks of conventional (SSRI or SNRI) antidepressant treatment.

Psychiatrists and GPs increasingly combine mirtazapine with an SSRI or SNRI antidepressant for patients whose depression does not respond to a single antidepressant.

The study, funded by the National Institute for Health Research, also found that patients taking mirtazapine in combination with another antidepressant had more adverse effects and were more likely to stop treatment than those who took an antidepressant and placebo.

Depression is one of the top five contributors to the global burden of disease and by 2030 is predicted to be the leading cause of disability in high income countries. People with depression are usually managed in primary care in the UK and antidepressants are often the first line of treatment. However, many patients do not respond to antidepressants.

The National Institute for Health and Care Excellence (NICE) advises GPs to reconsider treatment if there has been no response after 4-6 weeks of treatment. The practice of adding mirtazapine has grown as psychiatrists and GPs search for effective ways of treating those who don’t respond to a single antidepressant. Previous small-scale studies had shown that this combination might be effective.

Dr David Kessler from the Centres for Academic Mental Health and Academic Primary Care at the University of Bristol, and lead author of the study, said:

“Half of patients in primary care who take antidepressants remain depressed despite sticking to their treatment, yet there is little evidence about how to treat those for whom the drugs don’t work.

“Our study has found that there is unlikely to be a clinically important benefit for mirtazapine over placebo in addition to an SSRI or SNRI antidepressant in primary care patients with treatment resistant depression, and that the combination is not well tolerated. We recommend that GPs think very carefully before adding mirtazapine as a second antidepressant in this group of patients. This is particularly important when there are clear alternatives such as cognitive behavioural therapy, which has been shown to be effective in this group of patients.”

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There is a clear need for guidance about the best way to improve the outcome of depression treated in primary care, especially when the first treatment has not worked

Professor Ian Anderson from The University of Manchesteer said: "There is a clear need for guidance about the best way to improve the outcome of depression treated in primary care, especially when the first treatment has not worked. Probably the best way to summarise the outcome of this study is that it provided weak evidence of a small benefit from the combination of mirtazapine with an SSRI/SNRI antidepressant compared with continuing the SSR/SNRI alone, but at the expense of poorer tolerability.

"In a primary care context, the possible marginal benefit we found in the short-term does not support using this combination as a routine strategy. However, it doesn’t exclude useful benefit in other contexts, and at other doses, or in individual patients. This study provides important evidence about the mirtazapine-SSRI/SNRI combination in the setting and way in which it was studied, but we need to be careful not to take it as the final word in all situations."

MIRtazapine added to SSRIs or SNRIs for Treatment Resistant Depression in Primary Care: a placebo controlled randomised trial (MIR) is available here